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  • CLASSES

    Platelet Reducing Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral agent for the treatment of essential thrombocythemia and thrombocytocytosis secondary to myeloproliferative disorders; reduces elevated platelet counts and the risk of thrombosis in patients without affecting white or red blood cells or promoting the development of leukemia.

    COMMON BRAND NAMES

    Agrylin

    HOW SUPPLIED

    Agrylin/Anagrelide Hydrochloride Oral Cap: 0.5mg, 1mg

    DOSAGE & INDICATIONS

    For the treatment of thrombocytosis due to myeloproliferative disorders such as essential thrombocythemia, polycythemia vera, or chronic myelogenous leukemia (CML).
    NOTE: Anagrelide has been designated an orphan drug by the FDA for these indications.
    NOTE: Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. The time to complete response, defined as platelet count 600,000 cells/microliter or less, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, platelet counts typically will start to rise within 4 days and return to baseline concentrations in 1 to 2 weeks, possibly rebounding above baseline values.
    Oral dosage
    Adults

    0.5 mg PO 4 times daily or 1 mg PO twice daily for at least 1 week, then titrate dose to maintain target platelet count below 600,000 cells/microliter, and ideally between 150,000 cells/microliter to 400,000 cells/microliter. Do not increase the dose by more than 0.5 mg/day in any 1 week. Typical dose range is 1.5 to 3 mg/day. The maximum dosage is 2.5 mg/dose or 10 mg/day. Monitor platelet counts every 2 days during the first week of treatment and at least weekly thereafter until the desired maintenance dosage is reached.

    Children 7 to 12 years and Adolescents

    0.5 mg PO once daily for at least 1 week, then titrate dose to maintain target platelet count below 600,000 cells/microliter, and ideally between 150,000 cells/microliter to 400,000 cells/microliter. Do not increase the dose by more than 0.5 mg/day in any 1 week. Typical dose range is 1.5 to 3 mg/day. The maximum dosage is 2.5 mg/dose or 10 mg/day. Monitor platelet counts every 2 days during the first week of treatment and at least weekly thereafter until the desired maintenance dosage is reached.

    MAXIMUM DOSAGE

    Adults

    2.5 mg/dose PO or 10 mg/day PO.

    Elderly

    2.5 mg/dose PO or 10 mg/day PO.

    Adolescents

    2.5 mg/dose PO or 10 mg/day PO.

    Children

    >= 7 years: 2.5 mg/dose PO or 10 mg/day PO.
    < 7 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Anagrelide should be avoided in patients with severe hepatic impairment. In patients with moderate hepatic impairment, initial dosing is 0.5 mg PO once daily. In patients who have tolerated therapy for one week, the dose may be increased in increments of no more than 0.5 mg/day in any 1-week. The potential risks and benefits of anagrelide therapy in patients with mild or moderate hepatic impairment should be assessed before treatment begins.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Anagrelide may be taken with or without food.

    STORAGE

    Agrylin:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Renal failure, renal impairment

    Anagrelide should be used cautiously in patients with pre-existing renal impairment; although, no specific dosage adjustments are recommended. Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) showed no significant effects on the pharmacokinetics of anagrelide. Anagrelide therapy requires clinical monitoring, including periodic assessment of renal function. Hematuria and renal failure have been reported with anagrelide therapy.

    Hepatic disease

    Avoid use of anagrelide in patients with severe hepatic impairment. Anagrelide should be used cautiously in patients with mild to moderate hepatic disease; exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment. The potential risks and benefits of anagrelide therapy in a patient with mild or moderate hepatic disease/impairment should be assessed before treatment begins. Monitor hepatic function, such as liver function tests (LFTs), before initiating treatment and periodically thereafter. In patients with moderate hepatic impairment, dose reduction is required and patients should be carefully monitored for QTc prolongation and other cardiovascular effects. In addition, elevated hepatic enzymes were observed rarely in patients receiving anagrelide. Patients with hepatic dysfunction should be monitored closely for signs of hepatic toxicity while receiving anagrelide.

    Heart failure

    Use anagrelide in patients with heart failure only when the benefits outweigh the risks. Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with NYHA Class III to Class IV congestive heart failure. Consider periodic monitoring with an electrocardiogram (ECG).

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Use anagrelide in patients with cardiac disease only when the benefits outweigh the risks. Use anagrelide with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Anagrelide increased the QTc interval and heart rate in healthy volunteers. Consider periodic monitoring with an electrocardiogram (ECG) in patients with heart failure, bradyarrhythmias, or electrolyte abnormalities. Torsade de pointes and ventricular tachycardia have been reported with anagrelide. Prior to initiation of therapy, obtain a cardiovascular examination, including an ECG, in all patients. During treatment, monitor patients for cardiovascular effects and evaluate as necessary.

    Bleeding

    Use of concomitant anagrelide and aspirin increased the risk for major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of anagrelide with aspirin, since bleeding risks may be increased. Monitor patients for signs or symptoms of bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, phosphodiesterase-3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).

    Eosinophilic pneumonia, pneumonitis

    Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide in postmarketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. If suspected, discontinue anagrelide and evaluate. Symptoms may improve after drug discontinuation.

    Geriatric

    Of the total number of subjects in clinical studies of anagrelide, 42.1% were 65 years of age and older and 14.9% were 75 years of age and older. No overall differences in safety or effectiveness were observed between geriatric and younger adult patients, but greater sensitivity to the effects of anagrelide in some geriatric individuals cannot be ruled out. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, medications such as anagrelide may cause thrombocytopenia and increase the risk of bleeding. Common side effects of platelet inhibitors include headache, dizziness, and vomiting. Concurrent use with aspirin, warfarin, or NSAIDs may increase the risk of bleeding.

    Pulmonary hypertension

    Evaluate patients for signs and symptoms of underlying cardiopulmonary disease before initiating and during anagrelide therapy. Cases of pulmonary hypertension have been reported in patients treated with anagrelide.[30163]

    Pregnancy

    Case reports of anagrelide use during pregnancy have not identified an associated risk of adverse maternal or fetal outcomes, major birth defects, or miscarriage. There are no adequate and well-controlled studies with anagrelide during human pregnancy. In animal embryo-fetal studies, delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide during organogenesis at doses substantially higher than the maximum human clinical dose of 10 mg/day. Delay or blockage of parturition, deaths of non-delivering pregnant rats and their fully developed fetuses, and increased mortality in delivered pups were observed in a pre- and post-natal study of anagrelide at doses 58 times that of human clinical doses in female rats. Thrombotic complications associated with thrombocythemia include stroke, deep vein thrombosis, or myocardial infarctions. In pregnant women, thrombocythemia is associated with an increased risk of miscarriage, stillbirth, and preeclampsia.[30163]

    Breast-feeding

    The presence of anagrelide in human milk, effects on the breastfed child, or effects on milk production are not known. Anagrelide or its metabolites have been detected in the milk of lactating rats. Due to the potential for serious adverse reactions in nursing infants, such as thrombocytopenia, breast-feeding is not recommended during anagrelide therapy and for one week following the last dose of anagrelide. [30163]

    Infertility

    Anagrelide may cause infertility in female patients. In fertility studies involving female rats that received doses higher than the recommended maximum human dose, anagrelide was associated with increased pre- and post-implantation loss and a reduction in the number of live embryos.[30163]

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 0-5.0
    heart failure / Delayed / 0-5.0
    arrhythmia exacerbation / Early / 0-5.0
    GI bleeding / Delayed / 0-5.0
    visual impairment / Early / 0-5.0
    ventricular tachycardia / Early / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0
    atrial fibrillation / Early / Incidence not known
    pericarditis / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    stroke / Early / Incidence not known
    AV block / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known

    Moderate

    palpitations / Early / 26.1-26.1
    edema / Delayed / 20.6-20.6
    dyspnea / Early / 11.9-11.9
    peripheral edema / Delayed / 8.5-8.5
    sinus tachycardia / Rapid / 7.5-7.5
    migraine / Early / 0-5.0
    orthostatic hypotension / Delayed / 0-5.0
    peripheral vasodilation / Rapid / 0-5.0
    angina / Early / 0-5.0
    hypertension / Early / 0-5.0
    lymphadenopathy / Delayed / 0-5.0
    anemia / Delayed / 0-5.0
    thrombocytopenia / Delayed / 0-5.0
    bleeding / Early / 0-5.0
    gastritis / Delayed / 0-5.0
    elevated hepatic enzymes / Delayed / 0-5.0
    constipation / Delayed / 0-5.0
    melena / Delayed / 0-5.0
    confusion / Early / 0-5.0
    depression / Delayed / 0-5.0
    amnesia / Delayed / 0-5.0
    dehydration / Delayed / 0-5.0
    amblyopia / Delayed / 0-5.0
    hematuria / Delayed / 0-5.0
    dysuria / Early / 0-5.0
    supraventricular tachycardia (SVT) / Early / 0-1.0
    QT prolongation / Rapid / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    headache / Early / 43.5-43.5
    diarrhea / Early / 25.7-25.7
    asthenia / Delayed / 23.1-23.1
    nausea / Early / 17.1-17.1
    abdominal pain / Early / 16.4-16.4
    dizziness / Early / 15.4-15.4
    flatulence / Early / 10.2-10.2
    vomiting / Early / 9.7-9.7
    fever / Early / 8.9-8.9
    rash / Early / 8.3-8.3
    urticaria / Rapid / 8.3-8.3
    anorexia / Delayed / 7.7-7.7
    pharyngitis / Delayed / 6.8-6.8
    malaise / Early / 6.4-6.4
    cough / Delayed / 6.3-6.3
    back pain / Delayed / 5.9-5.9
    paresthesias / Delayed / 5.9-5.9
    pruritus / Rapid / 5.5-5.5
    dyspepsia / Early / 5.2-5.2
    syncope / Early / 0-5.0
    rhinitis / Early / 0-5.0
    sinusitis / Delayed / 0-5.0
    epistaxis / Delayed / 0-5.0
    ecchymosis / Delayed / 0-5.0
    eructation / Early / 0-5.0
    drowsiness / Early / 0-5.0
    insomnia / Early / 0-5.0
    myalgia / Early / 0-5.0
    diplopia / Early / 0-5.0
    chills / Rapid / 0-5.0
    muscle cramps / Delayed / 0-5.0
    arthralgia / Delayed / 0-5.0
    alopecia / Delayed / 0-5.0
    photosensitivity / Delayed / 0-5.0
    tinnitus / Delayed / 0-5.0
    hypoesthesia / Delayed / 0-1.0
    fatigue / Early / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Acetaminophen: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
    ADP receptor antagonists: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Alfuzosin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include alfuzosin.
    Altretamine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as altretamine.
    Amiodarone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include amiodarone.
    Amitriptyline: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Amitriptyline; Chlordiazepoxide: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include clarithromycin.
    Antimetabolites: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    Antithrombin III: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
    Apixaban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Apomorphine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include apomorphine.
    Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
    Aripiprazole: (Moderate) Caution is advised if aripiprazole is administered with anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with use of anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include arsenic trioxide. In addition, anagrelide inhibits platelet aggregation at high doses. Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur.
    Artemether; Lumefantrine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include artemether; lumefantrine.
    Asenapine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include asenapine.
    Aspirin, ASA: (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol: (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Because anagrelide and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Omeprazole: (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Oxycodone: (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Aspirin, ASA; Pravastatin: (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
    Atazanavir: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as atazanavir, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Monitor for increased adverse effects if anagrelide is coadministered with atazanavir.
    Atazanavir; Cobicistat: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as atazanavir, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Monitor for increased adverse effects if anagrelide is coadministered with atazanavir.
    Atomoxetine: (Moderate) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include atomoxetine. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of TdP.
    Azithromycin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include azithromycin.
    Barbiturates: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, such as barbiturates, could theoretically increase the elimination of anagrelide and decrease the efficacy of anagrelide.
    Bedaquiline: (Major) Torsade de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an electrocardiogram (ECG), should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include bedaquiline.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and platelet inhibitors are used concomitantly. Coadministration of betrixaban and platelet inhibitors may increase the risk of bleeding.
    Bevacizumab: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include anagrelide.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include anagrelide.
    Bivalirudin: (Moderate) When used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), bivalirudin is intended for use with aspirin (300 to 325 mg/day PO) and has been studied only in patients receiving concomitant aspirin. Generally, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (other than aspirin). In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. According to the manufacturer, the safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. However, bivalirudin has been safely used as an alternative to heparin in combination with provisional use of platelet glycoprotein IIb/IIIa inhibitors during angioplasty (REPLACE-2). In addition, two major clinical trials have evaluated the use of bivalirudin in patients receiving streptokinase following acute myocardial infarction (HERO-1, HERO-2). Based on the these trials, bivalirudin may be considered an alternative to heparin therapy for use in combination with streptokinase for ST-elevation MI. Bivalirudin has not been sufficiently studied in combination with other more specific thrombolytics.
    Bupivacaine; Lidocaine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including lidocaine, could lead to increases in the serum concentrations of lidocaine and, thus, adverse effects. Patients receiving anagrelide and lidocaine concomitantly should be monitored for increased toxicity of lidocaine.
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with anagrelide. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of buprenorphine and anagrelide for cardiovascular effects and evaluate as necessary.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with anagrelide. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of buprenorphine and anagrelide for cardiovascular effects and evaluate as necessary.
    Caffeine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Caffeine; Ergotamine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects.
    Carbamazepine: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, such as carbamazepine, could theoretically increase the elimination of anagrelide and decrease its efficacy. Patients should be monitored for changes in efficacy if these drugs are coadministered.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and anagrelide; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were also observed in healthy subjects.
    Chlorambucil: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Chloroquine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include chloroquine.
    Chlorpromazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include chlorpromazine.
    Chondroitin; Glucosamine: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
    Cilostazol: (Moderate) Because anagrelide and cilostazol inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Cimetidine: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as cimetidine, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Patients should be monitored for increased adverse effects if these drugs are coadministered.
    Cinacalcet: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including cinacalcet, could lead to increases in the serum concentrations of cinacalcet and, thus, adverse effects. Monitor patients for an increase in toxicity of cinacalcet if anagrelide is coadministered.
    Ciprofloxacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Ciprofloxacin is associated with a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with anagrelide. In addition, anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as ciprofloxacin, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Patients should be monitored for increased adverse effects if anagrelide is coadministered with ciprofloxacin.
    Cisapride: (Severe) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. Because of the potential for TdP, concurrent use is contraindicated.
    Citalopram: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include citalopram. In addition, platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clarithromycin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include clarithromycin.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clomipramine: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Clozapine: (Moderate) Caution is advisable during concurrent use of anagrelide and clozapine. Anagrelide is an inhibitor of CYP1A2, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. When initiating clozapine or adding a mild or moderate CYP1A2 inhibitor to clozapine treatment, monitor for adverse reactions and consider reducing the clozapine dose if necessary. If the inhibitor is discontinued, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cod Liver Oil: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased. (Moderate) Cod liver oil contains vitamin A and may increase the risk of bleeding if coadministered with platelet inhibitors.
    Codeine; Phenylephrine; Promethazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Codeine; Promethazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Crizotinib: (Major) According to the manufacturer of anagrelide, coadministration with other medications that prolong the QT interval should be avoided. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Crizotinib has also been associated with QT prolongation.
    Dabigatran: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. In addition, a phase II trial, aspirin (81 mg or 325 mg) was randomly assigned to patients with atrial fibrillation receiving dabigatran (150 mg twice daily). Data obtained from logistic regression analysis suggest that the concomitant administration of aspirin and dabigatran may increase the risk of bleeding from 12% to 18% (81 mg aspirin) or 24% (325 mg aspirin). Monitor patients closely for signs of bleeding if dabigatran or anagrelide is given concomitantly with aspirin.
    Dalteparin: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Danaparoid: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Dasatinib: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include dasatinib. In addition, due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Defibrotide: (Severe) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Degarelix: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include degarelix.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as denileukin difitox.
    Desflurane: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Desipramine: (Minor) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Desirudin: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with anagrelide, assess the QTc interval before and after increasing the dosage of either medication. A cardiovascular exam, including ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients for cardiovascular effects and evaluate as necessary. Clinically relevant QTc prolongation may occur with deutetrabenazine. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Dextromethorphan; Promethazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Dextromethorphan; Quinidine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include quinidine.
    Dipyridamole: (Moderate) Because anagrelide and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Disopyramide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include disopyramide.
    Dofetilide: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). TdP and ventricular tachycardia have been reported during post-marketing use of anagrelide. Because of the potential for TdP, concurrent use is contraindicated.
    Dolasetron: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include dolasetron.
    Dolutegravir; Rilpivirine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include anagrelide.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include anagrelide.
    Doxepin: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Dronedarone: (Severe) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.
    Droperidol: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include droperidol.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any platelet inhibitors within 7 days. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    Duloxetine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including duloxetine, could lead to increases in the serum concentrations of these drugs and, thus, adverse effects. Patients receiving anagrelide and duloxetine concomitantly should be monitored for increased toxicity of duloxetine. Monitor the patient for signs of excessive serotonin activity. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, duloxetine and the concomitant serotonergic agent should be discontinued and symptomatic treatment should be initiated.
    Edoxaban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Efavirenz: (Major) If possible, avoid coadministration of efavirenz and anagrelide, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Efavirenz; Emtricitabine; Tenofovir: (Major) If possible, avoid coadministration of efavirenz and anagrelide, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) If possible, avoid coadministration of efavirenz and anagrelide, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include anagrelide.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
    Encorafenib: (Major) Avoid coadministration of encorafenib and anagrelide due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Enflurane: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Enoxaparin: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Eptifibatide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Eribulin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include eribulin.
    Erythromycin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include erythromycin.
    Erythromycin; Sulfisoxazole: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include erythromycin.
    Escitalopram: (Moderate) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as anagrelide, should be done with caution and close monitoring. In addition, platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Estramustine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as estramustine.
    Ezogabine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include ezogabine.
    Fingolimod: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include fingolimod.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Flecainide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include flecainide.
    Fluconazole: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include fluconazole.
    Fludarabine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Fluoxetine: (Major) Coadministration may increase the risk of QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with both anagrelide and fluoxetine. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients for cardiovascular effects and evaluate as necessary. In addition, platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Fluoxetine; Olanzapine: (Major) Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Monitor patients for cardiovascular effects during concurrent use. In addition, anagrelide has been shown to inhibit CYP1A2. Olanzapine is a CYP1A2 substrate. In theory, coadministration could lead to increases in the serum concentration of olanzapine and thus, adverse effects. (Major) Coadministration may increase the risk of QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with both anagrelide and fluoxetine. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients for cardiovascular effects and evaluate as necessary. In addition, platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Fluphenazine: (Minor) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include fluphenazine.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and anagrelide. Coadminister with caution. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as needed. Platelet aggregation may be impaired by fluvoxamine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking fluvoxamine with an antiplatelet medication and to promptly report any bleeding events to the practitioner. Lastly, anagrelide is partially metabolized by CYP1A2, and it also has demonstrated some inhibitory activity of CYP1A2. When anagrelide is coadministered with drugs that also are substrates of and inhibit CYP1A2, such as fluvoxamine, patients should be monitored for increased adverse effects of either drug.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Fondaparinux: (Moderate) lthough anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as anagrelide. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes TdP. Torsade de pointes (TdP) and ventricular tachycardia have also been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Garlic, Allium sativum: (Moderate) Use together with caution. Garlic produces clinically significant antiplatelet effects, and a risk for bleeding may occur if platelet inhibitors are given in combination with garlic.
    Gemifloxacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include gemifloxacin.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and anagrelide together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Additionally, monitor patients for cardiovascular effects during concomitant therapy and evaluate as necessary. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects taking anagrelide.
    Ginger, Zingiber officinale: (Moderate) Ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist so additive bleeding may occur if platelet inhibitors are given in combination with ginger, zingiber officinale.
    Ginkgo, Ginkgo biloba: (Major) Use Ginkgo biloba with caution in patients taking platelet inhibitors, as it can produce clinically-significant antiplatelet effects. A compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking Ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.
    Glasdegib: (Major) Do not use anagrelide with other drugs that prolong the QT interval, such as glasdegib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were observed in healthy subjects. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Goserelin: (Moderate) Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with goserelin include anagrelide.
    Granisetron: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include granisetron.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if coadministered with anagrelide. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea and platelet inhibitors are coadministered.
    Guarana: (Moderate) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    Halogenated Anesthetics: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Haloperidol: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include haloperidol.
    Halothane: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Heparin: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Histrelin: (Major) Do not use anagrelide with other drugs that prolong the QT interval such as histrelin. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and anagrelide. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include anagrelide.
    Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as platelet inhibitors; the risk of bleeding may be increased. If coadministration with platelet inhibitors is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
    Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as anagrelide may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Ibutilide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include ibutilide.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Iloperidone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include iloperidone.
    Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Moderate) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Imipramine: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Inamrinone: (Moderate) Anagrelide is an inhibitor of cAMP phosphodiesterase III. The effects of inamrinone, which is an inhibitor of cAMP phosphodiesterase isozyme in cardiac and vascular muscle, may be increased if coadministered with anagrelide.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and anagrelide due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anagrelide in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with anagrelide due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Additionally, monitor patients for cardiovascular effects during concomitant therapy and evaluate as necessary. Inotuzumab has been associated with QT interval prolongation. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects taking anagrelide.
    Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Isoflurane: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, including rifampin, could theoretically increase the elimination of anagrelide and decrease the efficacy of anagrelide. Patients should be monitored for changes in efficacy if anagrelide is coadministered with rifampin.
    Isoniazid, INH; Rifampin: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, including rifampin, could theoretically increase the elimination of anagrelide and decrease the efficacy of anagrelide. Patients should be monitored for changes in efficacy if anagrelide is coadministered with rifampin.
    Itraconazole: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include anagrelide.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with anagrelide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Ketoconazole: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include anagrelide.
    Lapatinib: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include lapatinib.
    Lenvatinib: (Major) Do not use anagrelide with lenvatinib due to the risk of QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Lepirudin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with lepirudin.
    Leuprolide: (Moderate) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include anagrelide.
    Leuprolide; Norethindrone: (Moderate) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with leuprolide include anagrelide.
    Levofloxacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include levofloxacin.
    Levomilnacipran: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Lidocaine: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including lidocaine, could lead to increases in the serum concentrations of lidocaine and, thus, adverse effects. Patients receiving anagrelide and lidocaine concomitantly should be monitored for increased toxicity of lidocaine.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with anagrelide. Lithium has been associated with QT prolongation. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Lofexidine: (Major) Avoid coadministration of lofexidine and anagrelide due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG for QT prolongation if coadministration is required. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy.
    Lomustine, CCNU: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as lomustine.
    Long-acting beta-agonists: (Moderate) Beta-agonists should be used cautiously and with close monitoring with anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with anagrelide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of loperamide and anagrelide for cardiovascular effects and evaluate as necessary.
    Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with anagrelide. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during coadministration of loperamide and anagrelide for cardiovascular effects and evaluate as necessary.
    Lopinavir; Ritonavir: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include lopinavir; ritonavir.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as anagrelide. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy.
    Maprotiline: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include maprotiline.
    Mefloquine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include mefloquine.
    Meperidine; Promethazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Mercaptopurine, 6-MP: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Methadone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include methadone.
    Methoxsalen: (Minor) Agents that affect platelet function, such as platelet inhibitors, could decrease the efficacy of methoxsalen when used during photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include anagrelide.
    Mexiletine: (Moderate) Anagrelide is partially metabolized by and inhibits CYP1A2. When anagrelide is coadministered with drugs that also are substrates of and inhibit CYP1A2, such as mexiletine, patients should be monitored for increased adverse effects of either drug.
    Midostaurin: (Major) The concomitant use of midostaurin and anagrelide may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Mifepristone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include mifepristone.
    Milnacipran: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
    Milrinone: (Moderate) Anagrelide is an inhibitor of cAMP phosphodiesterase III. The effects of milrinone, which is an inhibitor of cAMP phosphodiesterase isozyme in cardiac and vascular muscle, may be increased if coadministered with anagrelide.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and anagrelide. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Moxifloxacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include moxifloxacin.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with anagrelide as significant prolongation of the QT interval may occur. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    Norfloxacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Norfloxacin is associated with a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with anagrelide. In addition, anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as norfloxacin, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Patients should be monitored for increased adverse effects if anagrelide is coadministered with norfloxacin.
    Nortriptyline: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as anagrelide. Therapeutic monitoring is recommended with coadministration.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Octreotide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include octreotide.
    Ofloxacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include ofloxacin.
    Olanzapine: (Major) Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Monitor patients for cardiovascular effects during concurrent use. In addition, anagrelide has been shown to inhibit CYP1A2. Olanzapine is a CYP1A2 substrate. In theory, coadministration could lead to increases in the serum concentration of olanzapine and thus, adverse effects.
    Ondansetron: (Major) If ondansetron and anagrelide must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Osimertinib: (Major) Do not use anagrelide with other drugs that prolong the QT interval. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects who received anagrelide.
    Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin and anagrelide concomitantly; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience. Ventricular tachycardia and TdP have also been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects who received anagrelide.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Do not use anagrelide with other drugs that prolong the QT interval. Torsade de pointes and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include anagrelide.
    Paroxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Pasireotide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include pasireotide.
    Pazopanib: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include pazopanib.
    Pegaspargase: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects, such as bleeding, associated with increased exposure to anagrelide if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor, while anagrelide is a CYP1A2 substrate.
    Pentamidine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include pentamidine.
    Pentosan: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Pentostatin: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Pentoxifylline: (Moderate) A potential additive risk for bleeding exists if platelet inhibitors are given in combination with other agents that affect hemostasis such as pentoxifylline.
    Perphenazine: (Minor) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include perphenazine.
    Perphenazine; Amitriptyline: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide. (Minor) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include perphenazine.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phenylephrine; Promethazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Photosensitizing agents: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Coadministration may increase the risk for QT prolongation. If coadministration cannot be avoided, a cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported during post-marketing use of anagrelide. Because of the potential for TdP, concurrent use is contraindicated.
    Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Porfimer: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Posaconazole: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include posaconazole.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include anagrelide.
    Procainamide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include procainamide.
    Prochlorperazine: (Minor) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include prochlorperazine.
    Promethazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include promethazine. Promethazine carries a possible risk of QT prolongation.
    Propafenone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include propafenone.
    Protriptyline: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Purine analogs: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Quetiapine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include quetiapine.
    Quinidine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include quinidine.
    Ranolazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include ranolazine.
    Rasagiline: (Major) Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant anagrelide, resulting in the potential for increased adverse events. Dosage adjustments are required when rasagiline is coadministered with a CYP1A2 inhibitor like anagrelide. If anagrelide is discontinued, the dose of rasagiline may need to be adjusted upward. Monitor therapeutic effect closely.
    Ribociclib: (Major) Avoid coadministration of ribociclib with anagrelide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with anagrelide due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, including rifampin, could theoretically increase the elimination of anagrelide and decrease the efficacy of anagrelide. Patients should be monitored for changes in efficacy if anagrelide is coadministered with rifampin.
    Rilpivirine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
    Risperidone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include risperidone.
    Rivaroxaban: (Major) Avoid concurrent administration of platelet inhibitors such as anagrelide with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
    Romidepsin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include romidepsin.
    Ropinirole: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including ropinirole, could lead to increases in the serum concentrations of ropinirole and, thus, adverse effects. Patients receiving anagrelide and ropinirole concomitantly should be monitored for increased toxicity of ropinirole.
    Rucaparib: (Moderate) Monitor for cardiovascular events and titrate anagrelide doses accordingly if coadministration with rucaparib is necessary. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were also observed in healthy subjects. Anagrelide is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Drugs that inhibit CYP1A2 could increase anagrelide exposure.
    Saquinavir: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include saquinavir.
    Selegiline: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including selegiline, could lead to increases in the serum concentration of selegiline and thus, adverse effects. Monitor for increased toxicity of selegiline.
    Sertraline: (Major) Coadministration of sertraline and anagrelide should be avoided if possible due to the potential for QT prolongation and torsade de pointes (TdP). There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Sevoflurane: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include halogenated anesthetics.
    Short-acting beta-agonists: (Minor) Beta-agonists should be used cautiously and with close monitoring with anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. This risk may be more clinically significant with long-acting beta-agonists (i.e., formoterol, arformoterol, indacaterol, olodaterol, salmeterol, umeclidinium; vilanterol) than with short-acting beta-agonists. Beta-agonists should be administered with caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with platelet inhibitors especially if used within the 3 weeks prior to the procedure.
    Solifenacin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include solifenacin.
    Sorafenib: (Major) Do not use anagrelide with sorafenib due to the risk of QT prolongation and torsade de pointes (TdP). Torsade de pointes and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include sotalol.
    Sulfinpyrazone: (Major) Sulfinpyrazone, when used as a uricosuric agent should be avoided when possible with concurrent platelet inhibitors due to potential for additive antiplatelet effects and increased bleeding risk.
    Sunitinib: (Major) Do not use anagrelide with other drugs that prolong the QT interval, such as sunitinib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Sunitinib can also cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including TdP.
    Tacrine: (Moderate) Anagrelide is partially metabolized by and may inhibit CYP1A2. When anagrelide is coadministered with drugs that are also substrates of and inhibit CYP1A2, such as tacrine, patients should be monitored for increased adverse effects of either drug.
    Tacrolimus: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include tacrolimus.
    Tamoxifen: (Major) Do not use anagrelide with tamoxifen due to the risk of QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses.
    Telavancin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include telavancin.
    Telithromycin: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include telithromycin.
    Teriflunomide: (Moderate) Use caution when administering teriflunomide and anagrelide concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as anagrelide, may decrease anagrelide exposure and lead to a reduction in efficacy. Monitor platelet counts.
    Tetrabenazine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include tetrabenazine.
    Theophylline, Aminophylline: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including aminophylline, could lead to increases in the serum concentrations of aminophylline and thus, adverse effects. Patients receiving anagrelide and aminophylline concomitantly should be monitored for increased toxicity of aminophylline. (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including theophylline, could lead to increases in the serum concentrations of theophylline and thus, adverse effects. Patients receiving anagrelide and theophylline concomitantly should be monitored for increased toxicity of theophylline.
    Thiabendazole: (Moderate) Thiabendazole is a potent inhibitor of CYP1A2 hepatic enzymes. Anagrelide is partially metabolized by CYP1A2. Coadministration may decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Coadminsiter with caution and monitor patients closely.
    Thioguanine, 6-TG: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Thioridazine: (Severe) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation andTdP and is contraindicated for use with other drugs that are known to prolong the QT interval.
    Thrombolytic Agents: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
    Tinzaparin: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Tirofiban: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
    Tizanidine: (Moderate) Avoid concomitant use of tizanidine and anagrelide as increased serum concentrations of tizanidine may occur. If use together is necessary, initiate tizanidine with the 2 mg dose and increase daily in 2 to 4 mg increments based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate; anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction.
    Tolterodine: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include tolterodine.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Toremifene: (Major) Avoid coadministration of anagrelide with toremifene due to the risk of additive QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trazodone: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include trazodone. In addition, platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Treprostinil: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with anagrelide. Treprostinil inhibits platelet aggregation; anagrelide is a platelet inhibitor. Coadministration increases the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as tretinoin.
    Trifluoperazine: (Minor) Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation that should be used cautiously with anagrelide include trifluoperazine.
    Trimipramine: (Moderate) Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP and should be used cautiously with anagrelide.
    Triptorelin: (Moderate) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with triptorelin include anagrelide.
    Vandetanib: (Major) Do not use anagrelide with vandetanib due to the risk of QT prolongation and torsade de pointes (TdP). Torsade de pointes and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Vandetanib can also prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
    Vardenafil: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include vardenafil.
    Vemurafenib: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Vemurafenib is associated with a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with anagrelide. In addition, concomitant use of vemurafenib and anagrelide may result in increased anagrelide concentrations. Vemurafenib is a CYP1A2 inhibitor and anagrelide is a CYP1A2 substrate. Anagrelide inhibits platelet aggregation at high doses. Patients should be monitored for toxicity. Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when anagrelide is used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with a platelet inhibitor and to promptly report any bleeding events to the practitioner. Also, torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include venlafaxine.
    Verteporfin: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
    Vorapaxar: (Moderate) Because vorapaxar and anagrelide inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Voriconazole: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include voriconazole.
    Vorinostat: (Major) Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors. Also, torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include vorinostat.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Warfarin: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, cilostazol, clopidogrel, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), anticoagulants (e.g., heparin, warfarin), or NSAIDs. Warfarin is a substrate of CYP1A2; anagrelide has been shown to inhibit CYP1A2. Monitor patients for increased therapeutic effect of warfarin, including an increase in the INR, if these drugs are coadministered. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
    Zileuton: (Moderate) Anagrelide is partially metabolized by and may inhibit CYP1A2. When anagrelide is coadministered with drugs that also are substrates of and inhibit CYP1A2, such as zileuton, patients should be monitored for increased adverse effects of either drug.
    Ziprasidone: (Major) Avoid use of anagrelide with other drugs that prolong the QT interval, such as ziprasidone. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Case reports of anagrelide use during pregnancy have not identified an associated risk of adverse maternal or fetal outcomes, major birth defects, or miscarriage. There are no adequate and well-controlled studies with anagrelide during human pregnancy. In animal embryo-fetal studies, delayed development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide during organogenesis at doses substantially higher than the maximum human clinical dose of 10 mg/day. Delay or blockage of parturition, deaths of non-delivering pregnant rats and their fully developed fetuses, and increased mortality in delivered pups were observed in a pre- and post-natal study of anagrelide at doses 58 times that of human clinical doses in female rats. Thrombotic complications associated with thrombocythemia include stroke, deep vein thrombosis, or myocardial infarctions. In pregnant women, thrombocythemia is associated with an increased risk of miscarriage, stillbirth, and preeclampsia.[30163]

    The presence of anagrelide in human milk, effects on the breastfed child, or effects on milk production are not known. Anagrelide or its metabolites have been detected in the milk of lactating rats. Due to the potential for serious adverse reactions in nursing infants, such as thrombocytopenia, breast-feeding is not recommended during anagrelide therapy and for one week following the last dose of anagrelide. [30163]

    MECHANISM OF ACTION

    Anagrelide exerts a thrombocytopenic effect and also inhibits platelet aggregation. The thrombocytopenic effect appears to be a result of inhibiting megakaryocyte development in the late, postmitotic stage. In vitro, anagrelide altered maturation stage, size, and ploidy of developing megakaryocytes. Anagrelide does not appear to alter megakaryocyte progenitor cells or mitotic expansion of developing megakaryocyte precursors. The thrombocytopenic effects of anagrelide appear to be specific for humans. Clinically, anagrelide lowers platelet counts and reduces thrombosis as well as thrombo-hemorrhagic symptoms associated with thrombocythemia.
     
    At dosages higher than those required to produce thrombocytopenia in humans, anagrelide affects platelet aggregation. The drug inhibits platelet aggregation by inhibiting cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. These actions increase platelet concentrations of cyclic adenosine monophosphate (cAMP). Anagrelide also inhibits collagen-induced platelet aggregation. Resistance to the drug effect does not appear to occur. Anagrelide does not produce significant changes in red cell or white cell counts or in coagulation parameters.

    PHARMACOKINETICS

    Anagrelide is administered orally. It is extensively metabolized to an active metabolite, 3-hydroxy-anagrelide, which is then metabolized by CYP1A2 to an inactive metabolite. Less than 1% of the administered dose is excreted unchanged in the urine. Approximately 3% and 16% to 20% of the administered dose is recovered as the active metabolite and inactive metabolite, respectively.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2
    Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Anagrelide shows limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates.

    Oral Route

    Following oral administration, at least 70% of the anagrelide dose is absorbed from the gastrointestinal tract. In fasted patients, anagrelide peak plasma concentrations occur about 1 hour after administration. Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC (total exposure) by 20%. The available plasma concentration time data at steady state in patients showed that neither anagrelide nor the active metabolite, 3-hydroxy-anagrelide, accumulate in plasma after repeated administration. The plasma elimination half-lives are approximately 1.5 hours and 2.5 hours for anagrelide and the active metabolite, respectively.